Perhaps the most basic division in the pain system is between sensory receptors with myelinated (Asigma) and those with unmyelinated (C) afferent fibers. Pain evoked by the activation of these two nociceptor types feels different and the two nociceptor types have been implicated in different kinds of clinical pain. Previous work demonstrated that these two nociceptor types are differentially activated by using different rates of noxious radiant heating of the hindpaw of the rat. Using a behavioral analgesiometric model based on this distinction, the previous supported work also demonstrated clear differences in the effects of analgesic treatments, such as opiates, on nociceptive responses evoked by these two nociceptor types. Work proposed in this application would extend this study by examining and comparing the neurochemistry and neuropharmacology of the two nociceptor types at the first synapse as they convey information to the central nervous system. This will be accomplished by measuring the release of putative neurotransmitters from presynaptic terminals and subsequent activation of neurotransmitter receptors on postsynaptic cells as evoked by selective activation of either Asigma or C fiber nociceptors. In this way, the differential use of neurotransmitters by different nociceptor types can be determined. In addition, serotonergic, noradrenergic, and opioid agents will be applied to determine whether part of the nociceptor-selective analgesic effects of these agents may be mediated through inhibition of the release of neurotransmitters from presynaptic spinal terminals of the nociceptors. These studies should provide important information as the mechanisms underlying the differential modulation of Asigma and C fiber mediated nociception. Since these two types of nociceptors probably mediate different kinds of clinical pain, a better understanding of their basic properties should lead to better targeting of analgesic drugs for specific types of pain, reducing the need for broad analgesic approaches, such as systemic application of opiates.